IL-12 signaling pathway
IL-12 is a key immunoregulatory cytokine
that coordinates innate and adaptive immune response. Major event of
IL-12 signaling is activation of Signal
transducers and activators of transcription (STATs), mainly STAT4, to promote differentiation of native CD4+T cells into T-helper
(Th) 1 cells, NK cellular cytotoxicity and T cell proliferation .
The main role of IL-12 is activation of
production. Upon binding to its receptor, IL-12
activates Janus family kinases Tyk2 and JAK2. IL-12RB1 binds
the Tyk2, whereas
associates with JAK2. JAK2
phosphorylates the tyrosine residues of STAT3 and STAT4. They
translocate to the nucleus and bind to the promoter site of IFN-gamma.
STAT4 also recruits
promoter , , .
Upon IL-12 action, STAT4 also induces transcription of IL-12RB2 and IL-18R1, that
leads to amplification of IL-12 signaling and
T-helper 1 cell differentiation , , , , . Also, IL-12 promotes expression of IRF1 and IRF4 in a
STAT4-dependent manner , .
In addition, IL-12 promotes expression of
IL-2R alpha chain by
recruiting STAT4 and c-Jun to the promoter of
IL-2R alpha chain and thereby
enhancing T cell proliferation , .
In NK cells, IL-12 induced cytotoxic events
by STAT4 activation of Perforin gene at its promoter .
And lastly, IL-12-induced
STAT4 activation leading to expression of
responsible for P-selectin ligand formation. This auguments
cell adhesion during T cell differentiation , , , .
IL-12 has the
capacity to induce STAT5 protein. JAK2 activation by IL-12 receptor induces
phosphorylation thus promoting cellular proliferation . However, there is
evidence that STAT5A can suppress IL-12-induced T-helper 1 cell differentiation through
the induction of SOCS3 expression. SOCS3 inhibits IL-12 signaling by binding to the
STAT4 docking site of the IL-12RB2
subunit , .
Another negative regulator of IL-12 signaling is PIAS2. It binds to
STAT4 and represses its transcriptional
It was shown that STAT4 undergoes
proteasomal degradation (see proteasomal protein catabolic process during
identified as an ubiquitin E3 ligase that acts on STAT4 protein to cause its proteasome-mediated degradation see proteasomal protein catabolic process , .
IL-12 receptor Complex
Interleukin-12 receptor subunit beta-1
Interleukin-12 receptor subunit beta-2
Interleukin-18 receptor 1
IL-2R alpha chain
Interleukin-2 receptor subunit alpha
Interferon regulatory factor 1
Interferon regulatory factor 4
Tyrosine-protein kinase JAK2
PDZ and LIM domain protein 2
E3 SUMO-protein ligase PIAS2
Suppressor of cytokine signaling 3
Signal transducer and activator of transcription 3
Signal transducer and activator of transcription 4
Signal transducer and activator of transcription 5 Protein group
Signal transducer and activator of transcription 5A
Non-receptor tyrosine-protein kinase TYK2
Transcription factor AP-1
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